High rates of relapse to drug use after prolonged drug-free periods characterize the behavior of experienced heroin and cocaine users. The behavioral and neurochemical events that contribute to these high rates, however, are not well understood. Relapse can be induced in human subjects and laboratory animals by reexposure to the drug previously used, reexposure to environmental cues paired with drug self-administration, and by exposure to stress. We are using an animal model of relapse, a reinstatement model, to study brain systems and neurotransmitters involved in relapse induced by environmental stressors, conditioned drug cues and drug reexposure in heroin- and cocaine-experienced rats after prolonged drug-free periods. During the last year, we have studied the neurochemical mechanisms underlying the time-dependent changes in responsiveness to cocaine-associated cues following drug withdrawal. The main finding of this line of research is the identification of long-lasting alterations following withdrawal from cocaine in growth factors and glutamate receptor subunits in the brain that may mediate the time-dependent changes in responsiveness to cocaine cues. In other studies we have found a role for the stress hormone, corticosterone, in reinstatement of heroin seeking induced by acute food deprivation. Using an immediate early gene approach to study neuronal activation, we also have found that reinstatement of food deprivation induced by food deprivation is associated with neuronal activation in cortical brain areas.